In navigating the environment, animals must integrate disparate sources of sensory information to appropriately modulate behavior. In vertebrates, a well characterized motor behavior which is modulated by environmental stimuli is the startle response. The startle response is normally elicited by abrupt acoustic, tactile or vestibular stimuli and is inhibited by the prior presentation of a subthreshold non-startling stimulus, a phenomenon known as prepulse inhibition. The objective of this proposal is to identify genetic lesions which disrupt prepulse inhibition. To do this we will analyze regulation of the startle response in zebrafish mutants. We have found that in zebrafish larvae, prepulse inhibition reduces the probability of eliciting an acoustic startle response. The experiments in this proposal will: First, test the hypothesis that prepulse inhibition in zebrafish is homologous to prepulse inhibition in higher vertebrates. Second, isolate zebrafish genetic mutants with defects in prepulse inhibition of the startle response. The long term goal of this proposal is to define the genetic, molecular and cellular mechanisms underlying prepulse inhibition of the zebrafish startle response. Reduced prepulse inhibition of the startle response has been described in several complex psychiatric diseases in humans including attention deficit disorder and schizophrenia, however the genetic basis of disrupted prepulse inhibition in these disorders remains unknown. As the neural architecture mediating the startle response is similar in zebrafish and higher vertebrates, this therefore represents an excellent opportunity to further our understanding of prepulse inhibition.